Facioscapulohumeral muscular dystrophy (FSHD) is linked to either contraction of D4Z4 repeats on chromosome 4 or to mutations in the SMCHD1 gene, both of which result in the aberrant expression of the transcription factor DUX4. However, it is still difficult to correlate these genotypes with the phenotypes observed in patients. The authors of the present study have recently shown that mice with disrupted Fat1 functions exhibit FSHD-like phenotypes. They therefore investigated the expression of the human FAT1 gene in FSHD. They show that FAT1 expression is independent of DUX4 and observed that: (i) in control fetal human biopsies or in developing mouse embryos, FAT1 is expressed at lower levels in muscles which are affected at early stages of FSHD progression than in muscles which are affected later or are non-affected; (ii) in adult muscle biopsies FAT1 expression is lower in FSHD muscles compared to control muscles. The authors propose a revised model for FSHD in which FAT1 levels might play a role in determining which muscles will exhibit early and late disease onset whereas DUX4 may worsen the muscle phenotype.
